Abstract

• Gastro-oesophageal reflux disease (GORD) is the commonest chronic disease in Western countries. Symptomatic GORD is the strongest risk factor for the development of oesophageal adenocarcinoma with obesity and male sex also linked to the development of neoplasia at this site. Recent decades have seen a significant increase in the incidence of this highly lethal cancer among Western populations with Scotland having the highest recorded incidence worldwide.
• Human saliva has a high nitrite content derived from the entero-salivary recirculation of nitrate in our diet which has resulted from the increased use of nitrogenous fertilisers over the past 50-60 years.
• The luminal chemistry produced at the gastro-oesophageal junction (GOJ) when swallowed salivary nitrite reacts with gastric acid, and most notably the production of nitric oxide (NO), may explain most of the physiological abnormalities that contribute to the pathogenesis of GORD. NO has been shown to reduce lower oesophageal sphincter (LOS) pressure, impair oesophageal clearance, delay gastric emptying and may be the final mediator of transient lower oesophageal sphincter relaxations (TLOSRs). Previous studies to investigate the role of this luminal chemistry in the pathogenesis of GORD show conflicting results.
• In addition to the distal oesophageal acidification produced by traditional trans-sphincteric reflux, previous studies suggest ‘splaying open’ of the distal lower oesophageal sphincter following a meal may expose the gastric cardia and the most distal oesophageal squamous mucosa to the noxious effects of gastric acid.
• Although the gastric cardia is an important site of pathology in the upper gastrointestinal tract, it is a complex and poorly understood area. It has been proposed, from autopsy studies, that cardia mucosa itself may be pathological and in fact an ‘acquired cardia’ due to metaplasia of the most distal oesophageal squamous mucosa.
• A series of studies were designed to examine the effect of salivary nitrite on post-prandial GORD, gastro-oesophageal function and GOJ morphology in 20 healthy, asymptomatic adult volunteers using high-resolution pH manometry, an isotope gastric emptying breath testing and X-ray localisation of the squamo-columnar junction (SCJ).
• Despite an excellent range of salivary nitrite concentrations extending over and above the normal physiological range no effect of salivary nitrite on gastro-oesophageal reflux, function or morphology was demonstrated. However, the studies did confirm, for the first time using high-resolution manometry, that distal opening of the LOS occurs after a meal.
• The relationship of age and obesity to the SCJ position relative to the proximal border of the gastro-oesophageal high pressure zone (HPZ) was examined in 15 Helicobacter Pylori negative healthy volunteers. Strong negative correlations were seen between SCJ position relative to the proximal HPZ and increasing age, body mass index (BMI) and waist circumference (WC) respectively. These correlations were stronger in the male sub-group.
• In 25 healthy volunteers, parietal cell density was measured from endoscopic biopsies taken from the macroscopic SCJ, 1cm distal to the SCJ, the gastric body and the gastric antrum. Again, a strong negative correlation was seen between increasing age and parietal cell density at the SCJ. This effect was localised to the SCJ and not seen at the other biopsy sites.
• Our findings suggest that salivary nitrite does not alter gastro-oesophageal function, the integrity of the gastro-oesophageal barrier or gastro-oesophageal reflux in healthy volunteers. They confirm distal opening of the LOS after meals. The strong negative correlations between age and both SCJ position relative to the proximal HPZ and parietal cell density support the hypothesis of an ‘acquired’ cardia. The development of cardia mucosa may also be linked to obesity, visceral obesity and male sex.
• Future work could examine the carcinogenic effect of salivary nitrite and its luminal chemistry but this would require large scale epidemiological research. Further, larger clinical studies are needed to investigate the role of distal opening of the LOS after meals and to improve our understanding of the gastric cardia. Such studies should focus on the role of obesity and posture.